In Favor Of Fever

The US spends over 17% of income, two trillion dollars a year, on medicine, mostly on new intensive treatments. You might think this was because we long ago carefully studied all the simple cheap treatments, and got as much mileage as we could from them, so now must consider complex expensive treatments. You’d be very very wrong.

One of the commonest, and cheapest, forms of medicine is “antipyretics”, e.g. aspirin, for reducing temperature. You know you are getting “modern” medicine if, when sick, people take your temperature often, and give you antipyretics when “too hot.” Seeing this care, you can relax assured you are getting modern care.

Turns out, we hardly have any data on whether this helps, and what data we do have says it probably makes you sicker, except in a few rare situations like stoke or head injury. It seems we are very reluctant to give up the appearance of helping the sick, even if our “help” probably makes them sicker.

We also seem pretty uninterested in collecting the data needed to clarify this. The biggest randomized trial to date was stopped mid-trial because “there were seven deaths in people getting standard treatment and only one in those allowed to have fever, … [so] it would be unethical to allow any more patients to get standard treatment.” Yet standard treatment continues because others say not enough trials exist to justify changing standard treatment. Is that #$@%-ed up ethics or what? Details:

One of the hallmarks of infectious illness, a fever is not just uncomfortable. In some cases it can trigger fits and perhaps even brain damage. The usual response is to bring down the temperature with antipyretic drugs, such as aspirin. … It has long been acknowledged that such drugs could, in theory, be counterproductive – they do, after all, interfere with the body’s natural response to infection. But these qualms have been set aside for a variety of reasons: the need to relieve discomfort; fears about brain damage; time-honoured practice; and, some would say, the urge to be doing something rather than nothing. ..

But now there’s growing concern that these time-honoured approaches are at best misguided and at worst potentially life-threatening. … the idea that antipyretics can prevent fits in children is looking increasingly shaky. …

“[Fever is] very old, existing not only in mammals and birds but also in fishes, amphibians and reptiles.” … It now seems that many disease-fighting mechanisms work better in hotter conditions. … It has also become clear that fevers are bad news for many microbes. … [Researchers] compared the quantity of bacteria in blood samples at normal body temperature with those at 40 °C and found that levels plunged by almost 90 per cent after several hours’ exposure to the higher temperature.

… How does that extrapolate to real-life patients? Unfortunately … The few existing studies are mainly “observational” ones. … Observational studies done in the 1980s and 90s did suggest that antipyretics hinder, rather than help the body’s response to the common cold, chicken pox and malaria. More recently, … examining over 400 records, Barlow’s team [found] the more feverish the patient on admission, the better their chance of survival. …

There has … been one randomised trial … in patients in intensive care … In 2005, [researchers] … studied 82 critically ill patients who did not have head injuries or other problems that make a high temperature risky. Patients were randomised to get either the standard treatment of antipyretics if their temperature went past 38.5 °C, or only receiving the drugs if their temperature reached 40 °C. As the trial progressed, there were seven deaths in people getting standard treatment and only one in those allowed to have fever. Although this difference was not quite large enough to be statistically significant, the team felt compelled to call a halt, feeling it would be unethical to allow any more patients to get standard treatment. …

Menon, however, believes there is not enough evidence yet to change practice. “It’s one study.” … He points out that there is plenty of evidence to show a raised temperature is harmful to the brain after a head injury or stroke. … Many patients in intensive care due to an infection are so ill … because of their body’s excessive response to [microbes] – of which fever is a part. … Even doctors like Menon, however, acknowledge that antipyretics are probably overused for minor illnesses. …

In 2007 … guidelines from the UK’s … NICE … [said] antipyretics should be used only if the fever seemed to be causing a child distress. … Febrile convulsions … almost never cause any lasting harm … [and] cannot be prevented by antipyretics. … “Not many people changed their practice. … We need to do a large randomised trial – it is the only way we can find out for sure.”

To check on this article, I did a quick search for randomized trials of antipyretics. I found this, this, this, and this; none found a significant health benefit from antipyretics.

There is a treatment called “fever therapy” which was the first effective treatment for neurosyphilis. The developer won the Nobel Prize for it, and it was the “standard of care” for neurosyphilis for a couple of decades. It consisted of giving the patient malaria, letting them go through ~10 cycles of fever before curing the malaria with quinine.

There was a recent paper about the behavioral symptoms of autism temporarily resolving during an acute fever. I blogged about that result in the context of nitric oxide physiology (what I think is the final common pathway). I don’t think it is temperature per se that causes the effects, rather I think it is the high NO that usually accompanies fever (but whether there is high NO depends on the type of fever).

While it may be the standard treatment, every time my son or I have had a fever in the last few years, the medical practitioner has advised us not to use anything to bring down the fever except under unusual circumstances. These practitioners include internists in private practice, pediatricians in private practice, and even doctors at minor emergency clinics. Since this is a marked change from when I was young, (I’m 31), and is described to me as “modern medicine” by the practitioners, I don’t think this is a good example. I live in Dallas/Fort Worth and I’m not all that affluent, so it’s not like I’m getting cutting edge, trendy medicine.

Nonetheless, my quibbling does not gainsay the substance of Robin’s post.

Curt Adams

I read about the evidence that many pathogenic bacteria have trouble with febrile temperatures over a decade ago and switched to only using antipyretics if I really have to do something and I feel too lousy. My own experience is that I do indeed get better faster if I just let the fever run. I particularly notice it with sinus infections, which only seem to go away after I run a moderately high fever for a day or so.

In the absence of a clinical trial actively showing antipyretics help letting the fever run should be the preferred choice. Your body’s actions in response to any event that has occurred over evolutionary time should, typically, be one that benefits the genes. This is not one of those cases like consumption of fattening food where it’s likely that the innate responses could be maladaptive. The fact that we almost always run fevers when sick is pretty good evidence that, on average, fevers are beneficial to our life expectancy.

http://akinokure.blogspot.com agnostic

I wonder how far back the anti-fever practice goes. I remember reading an evolutionary argument for in general letting the fever take its course, way back in one of Paul Ewald’s books in the ’90s (probably Plague Time).

Here’s another example, which he learned about first-hand when he got dysentery. The symptom of diarrhea is not comfortable, just like having a fever. Should we therefore intervene (through drugs or whatever) to stop the person’s diarrhea? Obviously not — this symptom is our way of getting the pathogens out of the body. Preventing the symptom would only keep their concentration high and allow them to cause greater damage.

There are two mindsets to change here, neither an easy task:

1) Give less respect for man-made rationalistic solutions, and more respect for solutions that come from natural selection (thousands, perhaps hundreds of thousands of years of experience spanning the entire human race throughout).

2) Focus on longer-term well-being than shorter-term comfort. If someone complains about having a cough, sneezing, fever, or diarrhea, tell them to suck it up and deal with it, as it’s a necessary part of flushing out the germs that are making them sick.

Underachiever

Excellent arguments.

Doug S.

Obviously not — this symptom is our way of getting the pathogens out of the body. Preventing the symptom would only keep their concentration high and allow them to cause greater damage.

Counterargument: Diarrhea is the result of damage to the lower intestine caused by the infectious bacteria. It’s not part of the body’s defenses, and the harm caused by loss of fluids and impaired ability to absorb nutrients is much greater than the benefit of physically removing material from the body. It’s the opposite: a mechanism evolved by pathogens to spread themselves and remove other, competing bacteria from the gut. It’s also how cholera kills people: through diarrhea-induced dehydration.

http://entitledtoanopinion.wordpress.com TGGP

I was just about to say that. I read “Plague Time” fairly recently and that doesn’t sound like Ewald. He actually got his idea while sick after he reconsidered his previous theory about the body’s natural mechanisms and recognized it’s just diarrhea’s way of making more diarrhea. Having a better sanitation system which prevents diarrhea from spreading so easily from tainted water causes the disease to become less virulent. I don’t know what would result from inhibiting the symptoms of it though.

http://akinokure.blogspot.com agnostic

I and Ewald know that diarrhea is the pathogens’ way of getting to the next host. Do you agree or disagree — preventing diarrhea results in a higher concentration of pathogens in the current host than letting the diarrhea happen? Do you agree or disagree — a higher concentration of pathogens in the host causes greater long-term damage to overall health?

Keep your eye on the ball kids. A thing can serve more than one purpose — ridding the body of pathogens and thus lowering long-term damage, and by that very ridding, convey the pathogens to their next host.

If it’s not in Plague Time, then it’s in the more academic one, Evolution of Infectious Disease.

http://akinokure.blogspot.com agnostic

Re: cholera, notice what the treatment is that keeps people alive — allow diarrhea (to rid the body of pathogens), but give the host an IV rehydration solution. It is not to keep diarrhea from happening in the first place.

http://williambswift.blogspot.com/ billswift

Actually they are both accurate. I think the “diarrhea reaction” originally evolved to eliminate internal contaminants, then was “appropriated” by some pathogenic organisms as a way to spread.

http://daedalus2u.blogspot.com/ daedalus2u

Diarrhea is the response of the host. The host evolved the capacity to exhibit diarrhea. Virtually all organisms with a gut have the capacity to exhibit diarrhea.

Organisms didn’t evolve to avoid all bad things, they evolved to maximize survival and reproduction. Diarrhea may be fatal. Bacteria chewing at the gut until it perforates is orders of magude more likely to be fatal. Flushing out a gut that is filled with bacteria that are killing the cells that line the gut may kill the organism due to dehydration, but it may save the organism from a perforated gut.

Evolution configured the gut to try and minimize deaths due to dehydration while also minimizing deaths due to a perforated gut. What is minimized is the sum of deaths from both conditions. Because a perforated gut is virtually certain death, a fairly large number of deaths due to dehydration can be tolerated to prevent a perforated gut.

In other words, if the absence of diarrhea resulted in a perforated gut (and death) 90% of the time, but only 5% of the time in the presence of diarrhea, an organism would be better off inducing diarrhea that killed from dehydration 40% of the time because then diarrhea would be a great survival factor, changing 90% of deaths due to a perforated gut to 5% from a perforated gut and 40% from dehydration, a 50% reduction in deaths. A fabulously advantageous evolved feature.

halvorz

In the case of cholera, diarrhea is the disease. The only thing cholera toxin does is cause diarrhea, leading to dehydration. It does not damage your intestines, or any other tissues of your body. If you prevent the diarrhea from occurring, you have, in fact, cured the disease.

Anecdotally, I have an unusually low body temperature (sometimes as low as 96 degrees), and find I get sick quite often, despite being young and in great physical shape.

Interestingly, when I get a fever, there’s a point where my body temperature is 98.6 degrees, and I feel fantastic, despite snot and goo coming out of every orifice.

David C

I guessed WebMD would be a good approximation for what “modern medicine” believes. They write that aspirin should not be used to treat fever. Ibuprofen or acetaminophen can be used to reduce the symptoms of viral fevers, but not to actually treat the virus itself.

I think the problem is that most people wrongly associate feeling good with being well. This is not the case. Feeling well or feeling sick evolved just like everything else. How you feel when you are sick is a signal for you to behave a certain way, to rest and conserve “energy” so that “energy” can be allocated to things like the immune system.

In reality the body has a limited capacity to make ATP, and how that ATP is allocated is extremely important. One of the major allocations is between immediate consumption and repair of damaged proteins, DNA and so forth, or in the case of an infection, toward fighting the infection. ATP spent doing something else can’t be used to fight an infection, so when you are sick, your body tells you (with fatigue and by making you feel sick) that ATP should not be expended unless it is an emergency, such as if a bear starts chasing you. Your body will let you divert ATP to running from a bear, but during some conditions such as during sepsis, this can be fatal.

I discuss mitochondrial failure in the context of immune system activation. I think this is the mechanism for multiple organ failure during sepsis.

Nitrite (NO2-), previously viewed as a physiologically inert metabolite and biomarker of the endogenous vasodilator NO, was recently identified as an important biological NO reservoir in vasculature and tissues, where it contributes to hypoxic signaling, vasodilation, and cytoprotection after ischemia-reperfusion injury. Reduction of nitrite to NO may occur enzymatically at low pH and oxygen tension by deoxyhemoglobin, deoxymyoglobin, xanthine oxidase, mitochondrial complexes, or NO synthase (NOS). We show that nitrite treatment, in sharp contrast with the worsening effect of NOS inhibition, significantly attenuates hypothermia, mitochondrial damage, oxidative stress and dysfunction, tissue infarction, and mortality in a mouse shock model induced by a lethal tumor necrosis factor challenge. Mechanistically, nitrite-dependent protection was not associated with inhibition of mitochondrial complex I activity, as previously demonstrated for ischemia-reperfusion, but was largely abolished in mice deficient for the soluble guanylate cyclase (sGC) α1 subunit, one of the principal intracellular NO receptors and signal transducers in the cardiovasculature. Nitrite could also provide protection against toxicity induced by Gram-negative lipopolysaccharide, although higher doses were required. In conclusion, we show that nitrite can protect against toxicity in shock via sGC-dependent signaling, which may include hypoxic vasodilation necessary to maintain microcirculation and organ function, and cardioprotection.

http://daedalus2u.blogspot.com/ daedalus2u

Anon, very nice paper, thank you for the link.

Chris P

You might want to examine IV acetaminophen (Ofirmev) and its clinical trials in fever. IV ibuprofen (Caldolor) was approved in 2008 for treating fever, so the FDA thinks that this is a clinically meaningful outcome.

David S.

The argument here isn’t over whether we should treat fever under certain circumstances; the argument is over whether we should treat fever in most cases. FDA approval of fever-reduction methods has no bearing on how often someone’s disease or discomfort warrants such treatment.

http://www.boxerurkabustaiz.es dog

Sounds reasonable. Then we need some drug that relieves the discomfort without lowering the fever.

Fnord

I only have limited experience, but I don’t think I’ve seen doctors fever-reduction for the sake of fever reduction in adults for mild or moderate fevers (<~105 F), at least in adults.

Note that the Mayo Clinic guidelines for adults only say to take antipyretics "if you feel uncomfortable". And they discourage their use for minor fevers.

The linked randomized studies don't show much of a benefit for antipyretic, but they don't show a harm, either, so symptomatic treatment for patient comfort doesn't seem like a big problem.

Jess Riedel

Without any previous discussion, I asked my father, a practicing surgeon, what the standard treatment was for fevers in the hospital. Paraphrased, he said “Well, the fever is your body’s natural response to infection, so as a rule of thumb we do nothing. However, we will give antipyretics in case of (1) significant patient discomfort when we do not think bringing down the fever would introduce any substantial risks (which is most of the time) or (2) certain injuries or complicating illnesses (usually only indirectly related to the infection) which are exacerbated by high body temperatures.

Anthony

It may not be scientific (because n=1), but I’ve found that when I have the ‘flu, going to bed and turning the electric blanket up to “broil” works pretty well at shortening the time I’m sick.

J Bell

robin…why did you write Is that #$@%-ed up ethics or what? as opposed to “Is that fuck-ed up ethics or what?” Why are you so willing to be provocative with your ideas but you are scared to write the word “fuck”? It’s actually a serious question.